Polycystic kidney disease (PKD) is a common genetic disorder that is characterized by the presence of numerous fluid-filled cysts in the renal parenchyma. The cysts grow in size over time producing kidney enlargement and renal failure. Approximately half of the affected individuals develop end-stage renal disease requiring dialysis or kidney transplantation. Despite recent progress, no FDA-approved therapy is currently available to retard cyst growth. microRNAs (miRNAs) are short non-coding RNAs that inhibit gene expression. Aberrant miRNA expression is observed in numerous diseases and correcting miRNA expression has emerged as a novel therapeutic approach. Dysregulation of miRNA expression is observed in PKD, but whether miRNAs contribute to the pathogenesis of PKD is not known. In preliminary studies, we have identified specific miRNAs that promote kidney cyst growth. We found that members of the miR-17, miR-18 and miR-19 miRNA families are up-regulated in multiple mouse models of PKD. Using genetic approaches, we found that kidney-specific overexpression of the miR-17~92 miRNA cluster is sufficient to produce tubular cysts. Conversely, genetic inactivation of miR-17~92 from renal tubules of kidney-specific Kif3a mutant mice, an animal model of PKD, retards cyst growth, improves renal function and prolongs survival. These studies have established miR-17 and related miRNAs as new regulators of cyst growth in PKD. The studies provide a strong rationale to determine whether pharmaceutical inhibition of miR-17, miR-18 and miR-19 miRNA families retards cyst growth in PKD. In this application, we propose to test the feasibility of small antimirs against the miR-17, miR-18 and miR-19 families as therapeutic agents in PKD. If successful, the results will validate miR- 17/18/19 as new therapeutic targets in PKD, and set the stage to develop miR-17/18/19 inhibitors for pre- clinical testing.